Radiation therapy is an important treatment received by over 50% of cancer patients. Exposure to radiation during the treatment of breast and lung cancers frequently causes collateral damage to cardiac tissue (i.e., cardiotoxicity), which can limit the utility of radiation and overall long-term benefits of this therapeutic option. In patients who receive cardiac radiation, progressive heart disease, heart failure, and death can occur. Mounting evidence suggests that complex genetic modifiers contribute to the risk of radiation-induced toxicities in cancer patients, yet these genetic modifiers remain largely unknown and poorly understood. No genetic variants are currently used to guide radiation dose constraints to the heart, and no therapies currently exist to protect against radiation-induced cardiotoxicity. We have developed the first genetic model to identify heritable modifiers of radiation- induced cardiotoxicity, using a rat model with gene substitutions (consomic rats) to identify regions of the genome responsible for differences in cardiac radiation sensitivity between two rat strains. Our preliminary results indicate that it may be possible to identify individuals at higher risk for radiation- induced heart disease based upon the presence of an inheritable 25 Mb region of rat chromosome 3 (0.9% of the genome) that contains genetic variants that enhance radiation-induced cardiotoxicity. This model demonstrates that (A) mitochondrial-related gene pathways are highly differentially expressed in the sensitive versus resistant rats one week after localized cardiac radiation, (B) hypertrophy and decreased contractility is detected at 12 weeks after radiation in the more sensitive rats, and (C) by 20 weeks after radiation, large areas of myocardial necrosis are present in the more sensitive rats. Our model provides a framework to define important phenotypic changes that stem from genetic variants to enhance radiotoxicity from cardiac radiation. We hypothesize that genetic modifier(s) of radiation-induced cardiotoxicity reside within the 25 Mb candidate region that we have localized to rat chromosome 3. We further hypothesize that the genetic modifier(s) within the candidate region are mechanistically linked to cardiomyocyte mitochondrial dysfunction that leads to cardiotoxicity in the sensitive rats after radiation. To test these hypotheses, we will (1) Use genetic mapping to identify genetic variant(s) that enhance radiation-induced cardiotoxicity in the 25 Mb region of rat chromosome 3; (2) Identify the pathophysiological and genetic mechanism(s) underlying radiation-induced cardiotoxicity findings of altered mitochondrial gene expression, cardiac hypertrophy and decreased contractility, and increased cardiac necrosis associated with the 25 Mb region of rat chromosome 3; and (3) Test the efficacy of novel mitochondrial-targeted agents to prevent or mitigate radiation-induced cardiotoxicity.